Focal Interstitial Fibrosis Research Articles

Obesity cardiomyopathy could contribute to sudden cardiac death: a Japanese epidemiological morphological study

BackgroundWe aimed to clarify the existence and pathological features of obesity cardiomyopathy (OCM) in Japan using our series of autopsy cases.MethodsIn this retrospective autopsy study, OCM was defined as cardiac hypertrophy (≥ 400 g in men, ≥ 320 g in women) of unknown aetiology in individuals with obesity (body mass index [BMI] ≥ 25 kg/m2 according to the Japanese definition of obesity). We compared cases of OCM with those with obesity without cardiac hypertrophy (OB) and normal weight without cardiac hypertrophy (normal control). Macroscopically, heart weight and cardiac parameters, including epicardial adipose tissue, were measured. Fibrosis, cardiomyocyte diameter, and adipose tissue infiltration were analysed microscopically.ResultsOf the 294 cases, we identified 19 cases of OCM (6.5%) and compared them with the OB and normal control groups. Patients with OCM were slightly younger than non-OCM patients (p = 0.081). The median heart weight was significantly heavier in OCM cases than in OB cases (435 g, interquartile range [IQR] 408–515 g vs. 360 g, IQR 341–385 g). Macroscopically, OCM hearts had a “globoid” appearance with a thickened right ventricular outflow tract. Some OCM cases showed focal interstitial fibrosis in the left ventricle. Approximately half the OCM cases were diagnosed with sudden cardiac death (SCD), with significant differences.ConclusionsThe prevalence of OCM may be higher than expected in Japan, and this may be a specific pathological finding. Given that approximately half the cases of OCM were due to SCD, OCM may cause SCD, emphasizing the need to recognise and diagnose OCM.

Diagnostic Implication of Skin Tubercles in Choking Case: An Autopsy Case

Tuberous sclerosis is a genetic disorder that affects every organ system, has a diverse presentation and progression, and can be life threatening. The authors encountered a case of a choking death caused by a fragment of rice cake. The deceased was an inmate of a social welfare institution due to mental retardation. The deceased was a 60-year-old male, 170 cm in height, and weighed 74 kg. Autopsy revealed multiple tubercles on the face, undigested food material, including rice cake, in the stomach, cardiomegaly (460 g) with mild coronary atherosclerosis, fatty infiltration into the myocardium, severe pulmonary congestion and edema with froth in the bronchus, and a yellowishbrown mass in each kidney. The brain showed firmness of the cortex in the parietal lobe and blurring of the white-grey matter interface. Histologically, the kidney masses were consistent with angiomyolipoma, and the brain lesion revealed abnormal neurons and astrocytes with a ballooned appearance and glassy cytoplasm, suggestive of tuberous sclerosis. Fatty infiltration and focal interstitial fibrosis were observed in the heart. Toxicology results were negative. The authors determined that the autopsy findings were consistent with tuberous sclerosis and that it may have been the cause of mental retardation, which served as an indirect cause of choking.

#2027 Activation of histone deacetylase-1 in fibroblasts and pericytes induces renal interstitial fibrosis after ischemia-reperfusion injury

Abstract Background and Aims Following an acute kidney ischemic event the chromatin remodelling enzyme, histone deacetylase-1 (HDAC1), is activated in many cell types of the kidney including fibroblasts and pericytes. During kidney injury, the fibroblasts/pericytes differentiate into the myofibroblasts and produce extracellular matrix that can lead to a permanent decline in kidney function. Pharmacological inhibition of HDACs can attenuate ischemia-reperfusion-injury (IRI) mediated interstitial fibrosis. The hypothesis of this study was that fibroblast/pericyte HDAC1 activation promotes myofibroblast differentiation and interstitial fibrosis. Method Tamoxifen inducible, fibroblast/pericyte HDAC1 knockout (KO) mice (HDAC1Fl/Fl; Col1a2-CreEr) and littermate controls (HDAC1Fl/Fl) were used. Male and female mice were given tamoxifen by ip at 8-10 weeks of age and IRI or sham surgery completed after a 2-week tamoxifen washout period. A mild, 18 min, bilateral, warm IRI model was used, and samples collected over 4 weeks. Glomerular filtration rate (GFR) was assessed using transdermal FITC-Sinistrin clearance. In vitro experiments with kidney fibroblast cells (NRK49F) overexpressing empty vector or HDAC1 were used for RNA-sequencing to determine the HDAC1-dependent myofibroblast transcriptome. Results We confirmed that HDAC1 was knockdown in myofibroblast cells from KO mice with co-localization of HDAC1 and PDGFRβ or α-smooth muscle actin in the kidneys of IRI mice. Twenty-four hours post-surgery, all IRI mice exhibited 2-3 times increase in serum creatinine and a ∼50% reduction in GFR compared to sham mice (control IRI = 513 ± 129 μl /min/100 g body mass, control sham = 1010 ± 218, n = 4-5, p = 0.02; KO IRI = 529 ± 116, KO sham = 1187 ± 59 μl/min/100 g body mass, n = 4-5, p = 0.004). Subsequent GFR measurements over the next 4 weeks showed a gradual recovery of renal function of IRI mice starting at week 2 and fully restored to sham values by week 4. However, the male control IRI mice had significant focal interstitial fibrosis 2- and 4-weeks post injury (4-week data: sham = 0.3 ± 0.09 % of cortical area, IRI = 1.2 ± 0.2%, n = 6/group, p = 0.0011) but this was attenuated in the KO male IRI mice (sham = 0.4 ± 0.07% n = 4, IRI = 0.5 ± 0.1%, n = 7, p = 0.93). The female mice, regardless of genotype, had very little kidney damage or interstitial fibrosis at 4 weeks. Transcriptomes of NRK49F cells overexpressing HDAC1 had an upregulation of 55 genes related to pro-inflammatory cytokines and tumour necrosis factor signalling and downregulation of 367 genes related to cell junctions, cytoskeleton proteins, and cell adhesion compared to the empty vector control cells. Fibroblast proliferation rates were not statistically different among the groups, suggesting HDAC1 does not affect myofibroblast proliferation but rather pro-inflammatory gene expression. Conclusion In male mice, fibroblast/pericyte activation of HDAC1 leads to the production of pro-inflammatory cytokines that we predict will lead to immune cell infiltration and crosstalk that leads to the excessive production of interstitial fibrosis following IRI.

Differentiation Between Invasive Adenocarcinoma and Focal Interstitial Fibrosis among Persistent Pulmonary Part-solid Nodules: With Emphasis on the CT Morphologic Analysis.

Focal interstitial fibrosis (FIF) manifesting as a persistent part-solid nodule (PSN) has been mistakenly treated surgically due to similar imaging features to invasive adenocarcinoma (ADC). The purpose of this study was to observe predictive imaging features correlated with FIF through CT morphologic analysis. From January 2009 to December 2020, 44 patients with surgically proven FIF in a single institution were enrolled and compared with 88 ADC patients through propensity score matching. Patient characteristics and CT morphologic analysis of persistent PSNs were used to identify predictive imaging features of FIF. Receiver operating characteristic (ROC) curve analysis was used to quantify the performance of imaging features. A total of 132 patients with 132 PSNs (44 FIF, 88 ADC; mean age, 67.7±7.58; 75 females) were involved in our analysis. Multivariable analysis demonstrated that preserved peritumoral vascular margin (preserved vascular margin), preserved secondary pulmonary lobule margin (preserved lobular margin), and lower coronal to axial ratio (C/A ratio; cutoff: 1.005) were significant independent predictors of FIF (P<0.05). ROC curve analysis to evaluate the predictive value of the logistic model based on the imaging features of FIF, and the AUC value was 0.881. CT imaging features of preserved vascular margin, preserved lobular margin, and lower C/A ratio (cutoff, <1.005) might be helpful imaging features in discriminating FIF over ADC among persistent PSN in clinical practice.

Total glucosides of peony regulate toll-like receptor to inhibit inflammatory response in diabetic nephropathy

Diabetic nephropathy (DN) is a common chronic disease affecting people’s life. Total glucosides of peony (TGP) regulates TLR4/NF-κB activation. This study aims at investigating the underlying mechanism of TGP in DN treatment. A retrospective analysis of clinical data was conducted to observe periodic acid-silver metheramine (PASM) staining and detect the expression of TLR4 and VEGF in DN. Additionally, rats were injected with Streptozocin (STZ) (30–60 mg) according to the ratio of 45–65 mg/kg to establish DN model. 8 weeks later, rats of experimental group were intraperitoneally injected with TGP. Kidney was collected for HE staining to observe morphological changes. Fibronectin expression was detected by histochemistry and the level of TLR4/NF-κB pathway-related proteins and apoptosis were detected by Western blot. PASM staining revealed focal tubular atrophy and interstitial fibrosis in DN patients. The renal medulla gradually disappeared and infiltration increased in control group, while inflammatory cells decreased in experimental group. The expression of fibronectin, TLR4 and p-p65 was decreased after TGP treatment. TGP treatment significantly decreased fibronectin expression and TGP treatment-induced inhibition of NF-κB signaling enhanced apoptotic activation of HK-2 cells, which was partially reversed by TLR4 and NF-κB inhibitors. TGP can inhibit inflammatory response of DN via regulating TLR4/NF-κB.

Abstract 11836: A Rare Cause of Recurrent Myocardial Infarction: Genetic Testing Cracks the Case

A 29-year-old man presented to our institution with acute, severe substernal chest pain. An ECG on arrival revealed 3mm ST-elevations in the lateral leads with reciprocal depressions in the inferior leads. Troponin-I was above assay (&gt;50 ng/mL). Emergent coronary angiography showed normal coronary arteries, and left ventriculogram showed no wall motion abnormalities. A transthoracic echocardiogram showed normal biventricular size, wall thickness, and ejection fraction (EF). This was his fifth episode of chest pain over the past 10 years, consistent with prior presentations of ST-elevation myocardial infarction and angiographically normal coronary arteries. A prior cardiac magnetic resonance imaging (MRI, 6 years before the current presentation) revealed increased T2 signal intensity and subepicardial late gadolinium enhancement (LGE) in the septum, inferior, and inferolateral walls, suggestive of nonischemic acute myocardial injury. A repeat cardiac MRI during the current presentation showed mildly reduced biventricular systolic function (LVEF 52%, RVEF 36%), and again showed increased T2 signal intensity and subepicardial LGE involving the septum, inferior and inferolateral walls. The anterior and anterolateral walls were also now involved. Endomyocardial biopsy (EMB) showed focal interstitial fibrosis with no evidence of active myocarditis. On telemetry he was noted to have runs of non-sustained ventricular tachycardia (NSVT). Serologic evaluation was negative for parvovirus, cytomegalovirus, and Chagas disease. Erythrocyte sedimentation rate and C-reactive protein levels were normal. Genetic testing was performed at our newly established cardiovascular genetics program, which showed a pathogenic truncating mutation in the desmoplakin gene (DSP). DSP cardiomyopathy (CM) is an LV-predominant arrhythmogenic CM, which can present with episodic myocardial injury, and has a high disposition for ventricular arrhythmias with subepicardial LGE pattern often proceeding LV systolic dysfunction. A primary prevention implantable cardioverter-defibrillator was placed given extent of LGE and NSVT burden in the context of DSP variant. This case illustrates the importance of genetic testing in identifying rare CM phenotypes.

#5295 SECONDARY MEMBRANOUS NEPHROPATHY WITH IGA DEPOSITS IN A PATIENT WITH PRIMARY CILIARY DYSKINESIA

Abstract Background and Aims Membranous nephropathy and IgA nephropathy are two types of common glomerulonephritis worldwide. There are reports of the coexistence of these glomerulopathies, mostly with mesangial expansion and IgA deposits. Furthermore, primary ciliary dyskinesia is rarely associated to glomerulopathy. Thus, we report a case of a patient with primary ciliary dyskinesia with renal biopsy demonstrating membranous glomerulopathy associated with IgA and IgG deposits exclusively in glomerular basement membrane, without complement deposition. Method Case report. Results A 18 years-old man was referred from the nephropediatric outpatient clinic with subnephrotic hematuria and proteinuria. His medical history included a clinical diagnosis of primary ciliary dyskinesia due to a history of several respiratory infections since birth, asthma, rhinitis and bronchiectasis and a 15 years-old brother with a similar history. He was diagnosed with idiopathic thrombocytopenic purpura at age of one year-old and received prednisone. At 3 years-old he presented with nephrotic syndrome, hematuria and hypertension, and was treated with intravenous methylprednisolone and oral cyclophosphamide for three months. Renal biopsy demonstrated mesangial expansion and thickening of the glomerular basement membrane (GBM), without adequate material for immunofluorescence. Because proteinuria and hematuria persisted, the prednisone dose was increased to 2 mg/kg/day and cyclosporine was started. After 5 years on these medications, persisting with proteinuria, a second biopsy was performed and showed 16 glomeruli, three globally sclerosed and the others with diffuse thickening of the GBM, without other alterations, focal interstitial fibrosis and tubular atrophy and diffuse granular deposits of IgA 1+ and IgG 2+ along the GBM. Cyclosporine and prednisone were discontinued. At age of 18 years-old, he was admitted to adult glomerulonephritis clinic with significant developmental delay (weight 28.6kg and height 1.29m2), no edema and normal arterial blood pressure with RAAS inhibition. Laboratory tests: Hb 8.9 g/dL, serum iron 12 mcg/dL, Creatinine 0.7 mg/dL, albumine 2.3 g/dL. Serologies were negative for syphilis, hepatitis B and C, HIV, ANA and anti-DNA, with normal complement C3, C4 and C1q. Urinalysis revealed proteinuria 1+, hematuria 16.000/mL and proteinuria 1.400 mg/d. CT scan showed symmetrical bronchiectasis in both lungs, with mucoid endobronchial impingement and diffuse bronchial parietal thickening; and chronic post-thrombotic changes with calcified thrombi in the left renal vein, extending into the inferior vena cava. A third renal biopsy was performed showing 38 of 45 (84%) globally sclerosed glomeruli without mesangial matrix changes or capsular adhesions. GBM was thickened with spicules and holes and reactive podocytes. The tubulointerstitial compartment showed moderate atrophy and fibrosis (40-50%). Immunofluorescence microscopy evidenced strong immunoreactivity of IgG 3+/3+, IgA 3+/3+, Kappa 3+/3+ and Lambda 2+/3+, in granular pattern exclusively in GBM, without C3. Electron microscopy showed four sclerosed glomeruli, without deposits. Immunohistochemistry staining for IgG1 2+/3+, and it was negative for PLA2R, NELL-1, THSD7A, Exostosin-1 and 2, IgG 2, IgG3 and IgG4. The patient was maintained with supportive treatment, with RAAS inhibition and SGLT2 inhibitors, without immunosuppression. Conclusion This case highlights the codominance of IgG1 and IgA deposits along the MBG, without proliferation or mesangial deposition and without complement activation, in a patient with membranous nephropathy and primary ciliary dyskinesia, a condition rarely associated with glomerulopathies. Although rare, such renal biopsy findings reinforce the need for a better understanding of the different mechanisms of membranous nephritis, in addition to better understanding and management of treatment in this situation.

#3626 A CASE OF PODOCYTE DISEASE WITH AZOTEMIA FOLLOWING TREATMENT WITH INTRAVENOUS IBANDRONATE

Abstract Background and Aims Bisphosphonate use may induce several types of nephrotoxicity. There are many reports on pamidronate-associated glomerular disease, such as focal segmental glomerulosclerosis and zoledronate-associated acute tubular necrosis. However, there are limited reports on ibandronate-associated nephrotoxicity. Herein, we describe a case of podocyte disease accompanied with azotemia following intravenous administration of ibandronate. Method Case report Results An 88-year-old female was referred to the emergency room due to grade 4 edema that developed 1 month before. The patient was diagnosed with osteoporosis 20 months earlier, for which she received quarterly intravenous administration of ibandronate (3 mg). The last dose was administered 2 weeks ago. The patient had no history of diabetes, hypertension, or chronic kidney disease. Laboratory tests revealed heavy proteinuria with a protein/creatinine ratio (PCR) of 32 and hypoalbuminemia (1.9 g/dL) with elevated serum creatinine (sCr) (1.8 mg/dL). Values of serum complement and electrophoresis were within normal ranges. The renal ultrasonogram was unremarkable. A renal biopsy was performed and light microscopy showed mild mesangial hypercellularity and segmental amorphous collagenous deposition in the glomerulus (Fig. 1-A). The tubules revealed focal marked atrophy and interstitial fibrosis (Fig. 1-B). Immunofluorescence studies were unremarkable. Electron microscopy showed diffuse effacement of foot processes and no electron-dense deposit (Fig. 1-C), consistent with podocyte disease favoring focal segmental glomerulosclerosis. The patient was treated with tacrolimus and fimasartan. Steroid use was spared owing to severe osteoporosis. Three months later, the edema subsided and laboratory findings improved (PCR 0.64, serum albumin 4 g/dL, sCr 1.23 mg/dL). Conclusion Compared to pamidronate and zoledronate, ibandronate is more highly protein-bound with a significantly shorter renal tissue half life, which might explain the rarity of ibandronate-related nephrotoxicity. Contrary to the trend of other bisphosphonates nephropathies, our case showed simultaneous podocyte disease and tubule damage. We recommend close monitoring of proteinuria and renal function for prompt nephrotoxicity detection in patients treated with ibandronate.

Detection of Early Diffuse Myocardial Fibrosis and Inflammation in Chagas Cardiomyopathy with T1 Mapping and Extracellular Volume

Purpose To evaluate myocardial T1 mapping and extracellular volume (ECV) parameters in different stages of Chagas cardiomyopathy and determine whether they are predictive of disease severity and prognosis. Materials and Methods Prospectively enrolled participants (July 2013 to September 2016) underwent cine and late gadolinium enhancement (LGE) cardiac MRI and T1 mapping with a precontrast (native) or postcontrast modified Look-Locker sequence. The native T1 and ECV values were measured among subgroups that were based on disease severity (indeterminate, Chagas cardiomyopathy with preserved ejection fraction [CCpEF], Chagas cardiomyopathy with midrange ejection fraction [CCmrEF], and Chagas cardiomyopathy with reduced ejection fraction [CCrEF]). Cox proportional hazards regression and the Akaike information criterion were used to determine predictors of major cardiovascular events (cardioverter defibrillator implant, heart transplant, or death). Results In 107 participants (90 participants with Chagas disease [mean age ± SD, 55 years ± 11; 49 men] and 17 age- and sex-matched control participants), the left ventricular (LV) ejection fraction and the extent of focal and diffuse or interstitial fibrosis were correlated with disease severity. Participants with CCmrEF and participants with CCrEF showed significantly higher global native T1 and ECV values than participants in the indeterminate, CCpEF, and control groups (T1: 1072 msec ± 34 and 1073 msec ± 63 vs 1010 msec ± 41, 1005 msec ± 69, and 999 msec ± 46; ECV: 35.5% ± 3.6 and 35.0% ± 5.4 vs 25.3% ± 3.5, 28.2% ± 4.9, and 25.2% ± 2.2; both P < .001). Remote (LGE-negative areas) native T1 and ECV values were also higher (T1: 1056 msec ± 32 and 1071 msec ± 55 vs 1008 msec ± 41, 989 msec ± 96, and 999 msec ± 46; ECV: 30.2% ± 4.7 and 30.8% ± 7.4 vs 25.1% ± 3.5, 25.1% ± 3.7, and 25.0% ± 2.2; both P < .001). Abnormal remote ECV values (>30%) occurred in 12% of participants in the indeterminate group, which increased with disease severity. Nineteen combined outcomes were observed (median follow-up time: 43 months), and a remote native T1 value greater than 1100 msec was independently predictive of combined outcomes (hazard ratio, 12 [95% CI: 4.1, 34.2]; P < .001). Conclusion Myocardial native T1 and ECV values were correlated with Chagas disease severity and may serve as markers of myocardial involvement in Chagas cardiomyopathy that precede LGE and LV dysfunction. Keywords: MRI, Cardiac, Heart, Imaging Sequences, Chagas Cardiomyopathy Supplemental material is available for this article. © RSNA, 2023

Cadmium exposure induces histological damage and cytotoxicity in the cardiovascular system of mice.

Epidemiological studies have reported an association between chronic cadmium (Cd) exposure and increased cardiovascular risk; however, their causal relationship remains unclear. The aim of this study is to explore the effects of Cd exposure on the cardiac and arterial systems in mice. According to the concentration of cadmium chloride in drinking water, male mice were randomly divided into control and low-dose and high-dose Cd exposure groups. The intervention duration was 12 weeks. In cardiac tissues, Cd exposure led to focal necrosis, myofibril disarray, perivascular and interstitial fibrosis, and disorganized sarcomere structures. Cd also induced the apoptosis of cardiomyocytes and increased the expression levels of matrix metalloproteinase (MMP)-2 and MMP-14 in cardiac tissues. In the arterial tissues, Cd exposure damaged the intimal and medial layers of the aorta. Cd further reduced the viability of aortic smooth muscle cells in vitro. This study provides evidence for the Cd-induced damage of the cardiovascular system, which may contribute to various cardiovascular diseases.

Abstract 15317: An Unusual Case of Recurrent Chest Pain: Lymphocytic Myocarditis

Case Presentation: A 42-year-old male with a past medical history of recurrent myopericarditis treated with a combination of NSAIDs, colchicine, and steroids presented for left-sided chest pain. The pain first recurred when he attempted a prednisone taper and he was started on Anakinra. Upon presentation, physical examination and laboratory findings were within normal limits. Echocardiography and electrocardiogram were within normal limits. Cardiac magnetic resonance imaging (CMR) showed transmural enhancement of the basal-mid inferolateral segments and patchy mid-myocardial enhancement in the basal-mid anterolateral segments. Nuclear medicine PET showed FDG uptake in the basal anteroseptal, anterolateral, inferolateral, inferior, and apical segments suggestive of active inflammation. Initially, the diagnosis was thought to be recurrent myopericarditis of unknown etiology. Subsequent right heart catheterization with endomyocardial biopsy (EMB) showed mononuclear infiltrates in the interstitium associated with myocyte infiltration and focal moderate interstitial fibrosis. Due to his clinical, imaging, and pathologic findings, he was diagnosed with lymphocytic myocarditis. His anti-inflammatory therapy regimen was reinstated, and he was started on Mycophenolate Mofetil. On follow-up, the patient had significant symptomatic improvement. Discussion: Lymphocytic myocarditis is a pattern of myocardial inflammation that is typically associated with autoimmune and idiopathic causes. Myocarditis frequently manifests with signs and symptoms of heart failure, including chest pain, dyspnea, and arrhythmias. Diagnosis of myocarditis is often supported by CMR and FDG-PET findings, however, EMB is the gold standard for the diagnosis of myocarditis. Treatment is generally supportive, though immunomodulatory therapies have gained increased popularity due to benefits in treating symptoms and preventing complications of heart failure.

ACCELERATED GRANULOMATOUS LYMPHOCYTIC INTERSTITIAL LUNG DISEASE DUE TO COVID-19 IN A PATIENT WITH COMMON VARIABLE IMMUNODEFICIENCY PRESENTING WITH RECURRENT PNEUMOTHORACES

ACCELERATED GRANULOMATOUS LYMPHOCYTIC INTERSTITIAL LUNG DISEASE DUE TO COVID-19 IN A PATIENT WITH COMMON VARIABLE IMMUNODEFICIENCY PRESENTING WITH RECURRENT PNEUMOTHORACES

A CASE OF COMMON VARIABLE IMMUNODEFICIENCY (CVID) COMPLICATED BY GRANULOMATOUS LYMPHOCYTIC INTERSTITIAL LUNG DISEASE (GLILD) TRIGGERED BY RECENT COVID-19 INFECTION

A CASE OF COMMON VARIABLE IMMUNODEFICIENCY (CVID) COMPLICATED BY GRANULOMATOUS LYMPHOCYTIC INTERSTITIAL LUNG DISEASE (GLILD) TRIGGERED BY RECENT COVID-19 INFECTION

Etlingera elatior Flower Aqueous Extract Protects against Oxidative Stress-Induced Nephropathy in a Rat Model of Type 2 Diabetes.

Diabetes mellitus (DM) is a known systemic disease with increasing global prevalence and multi-organ complications including diabetic nephropathy (DN). The trend of using medicinal plants in the management of DM is increasing exponentially. Etlingera elatior is a medicinal plant that contains chemicals and antioxidants that delay the oxidation process. However, available data focusing on its use on DN are inconsistent and scarce. This study aims to investigate the antidiabetic and nephroprotective effects of E. elatior flower aqueous extract (EEAE) in a type 2 DM rat (T2DR) model. The T2DR model was developed using a combination of a high-fat diet (HFD) and a low dose of streptozotocin (STZ) at 35 mg/kg. Thirty-two Sprague Dawley male rats were randomly divided into four groups (n = 8): (1) control (normal rat), (2) T2DR (untreated-type 2 diabetic rat), (3) Met (250 mg/kg metformin-treated T2DR), and (4) EEAE (1000 mg/kg EEAE-treated T2DR). All treatments were administered orally for 6 weeks. EEAE significantly reduced fasting blood glucose (FBG), microalbuminuria, serum creatinine, and serum blood urea nitrogen. EEAE also reduced malondialdehyde (MDA) and enhanced the levels of antioxidant markers—superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and total antioxidant capacity (T-AOC). The inflammatory marker (interleukin (IL)-6) and fibrosis markers (transforming growth factor-beta (TGF-β), and connective tissue growth factor (CTGF)) were significantly decreased in the EEAE-treated group. The T2DR group developed DN, which was characterized by segmental sclerosis of the glomeruli associated with focal tubular atrophy and interstitial fibrosis. Interestingly, the histology of kidney tissue in the EEAE group was preserved. This effect was similar to that of the control drug metformin. In summary, the antidiabetic and nephroprotective effects might be related to the antioxidant properties and anti-inflammatory effects of the EEAE. The antidiabetic activity could be due to the presence of the active compound cyanidin-3-O-glycosides, which is an anthocyanin antioxidant, that is present in the EEAE. E. elatior has the potential to be developed as a natural source of antioxidants that can be used for the prevention or even the treatment of DM. These findings could lead to future research into the therapeutic use of E. elatior in alleviating the progression of DM and thus preventing nephropathy.

Proteomic Study of Low-Birth-Weight Nephropathy in Rats.

The hyperfiltration theory has been used to explain the mechanism of low birth weight (LBW)-related nephropathy. However, the molecular changes in the kidney proteome have not been defined in this disease, and early biomarkers are lacking. We investigated the molecular pathogenesis of LBW rats obtained by intraperitoneal injection of dexamethasone into pregnant animals. Normal-birth-weight (NBW) rats were used as controls. When the rats were four weeks old, the left kidneys were removed and used for comprehensive label-free proteomic studies. Following uninephrectomy, all rats were fed a high-salt diet until 9 weeks of age. Differences in the molecular composition of the kidney cortex were observed at the early step of LBW nephropathy pathogenesis. Untargeted quantitative proteomics showed that proteins involved in energy metabolism, such as oxidative phosphorylation (OXPHOS), the TCA cycle, and glycolysis, were specifically downregulated in the kidneys of LBW rats at four weeks. No pathological changes were detected at this early stage. Pathway analysis identified NEFL2 (NRF2) and RICTOR as potential upstream regulators. The search for biomarkers identified components of the mitochondrial respiratory chain, namely, ubiquinol-cytochrome c reductase complex subunits (UQCR7/11) and ATP5I/L, two components of mitochondrial F1FO-ATP synthase. These findings were further validated by immunohistology. At later stages of the disease process, the right kidneys revealed an increased frequency of focal segmental glomerulosclerosis lesions, interstitial fibrosis and tubular atrophy. Our findings revealed proteome changes in LBW rat kidneys and revealed a strong downregulation of specific mitochondrial respiratory chain proteins, such as UQCR7.

Differentiating focal interstitial fibrosis from adenocarcinoma in persistent pulmonary subsolid nodules (&gt; 5 mm and &lt; 20 mm): the role of coronal thin-section CT images

To investigate thin-section computed tomography (CT) features of pulmonary subsolid nodules (SSNs) with sizes between 5 and 20 mm to determine predictive factors for differentiating focal interstitial fibrosis (FIF) from adenocarcinoma. From January 2017 to December 2018, 169 patients who had persistent SSNs 5-20 mm in size and underwent preoperative nodule localization were enrolled. Patient characteristics and thin-section CT features of the SSNs were reviewed and compared between the FIF and adenocarcinoma groups. Univariable and multivariable analyses were used to identify predictive factors of malignancy. Receiver operating characteristic (ROC) curve analysis was used to quantify the performance of these factors. Among the 169 enrolled SSNs, 103 nodules (60.9%) presented as pure ground-glass opacities (GGOs), and 40 (23.7%) were FIFs. Between the FIF and adenocarcinoma groups, there were significant differences (p< 0.05) in nodule border, shape, thickness, and coronal/axial (C/A) ratio. Multivariable analysis demonstrated that a well-defined border, a nodule thickness >4.2, and a C/A ratio >0.62 were significant independent predictors of malignancy. The performance of a model that incorporated these three predictors in discriminating FIF from adenocarcinoma achieved a high area under the ROC curve (AUC, 0.979) and specificity (97.5%). For evaluating persistent SSNs 5-20 mm in size, the combination of a well-defined border, a nodule thickness > 4.2, and a C/A ratio > 0.62 is strongly correlated with malignancy. High accuracy and specificity can be achieved by using this predictive model. • Thin-section coronal images play an important role in differentiating FIF from adenocarcinoma. • The combination of a well-defined border, nodule thickness>4.2 mm, and C/A ratio >0.62 is associated with malignancy. • This predictive model may be helpful for managing persistent SSNs between 5 and 20 mm in size.

ES23.05 GGN Issues

As low-dose computed tomography (LDCT) is increasingly popular, the possibility of detecting ground-glass nodules (GGN) has also increased significantly, which was uncommon in the era of chest radiography as a regular health examination. Although the term GGN can be focal interstitial fibrosis, inflammation, hemorrhage and malignancies, we mainly focus on GGN that is pathologically malignant. A substantial proportion of GGNs detected at screening CT are transient [1]. It is important to avoid overtreatment of transient GGNs. The possibility of spontaneous regression of newly diagnosed GGN should always be considered before invasive treatment is decided. Several sets of guidelines are already available for the management of GGNs found on CT scans or via CT screening [2,3]. Obviously, there are differences in the recommendations of each guideline for some specific scenarios. One of the important reasons is that the correlation between radiographic appearance and histologic diagnosis is far from reliable [4]. Some people simply thought GGN referred to the site without blocking of alveolar cavity pathologically, and ground-glass opacity (GGO) components therefore represented the lepidic growth pattern of adenocarcinoma. However, both lepidic and non-lepidic growth patterns can present as GGNs on CT images [5]. So, GGO is a rather unspecific radiologic feature involving various pathologic conditions. The radiologic feature of GGO has a significant impact on clinical results. Several studies have revealed that the presence of a GGO component was a significantly favorable prognostic factor in early-stage NSCLC [6,7]. In Fu’s study, the 5-year RFS rates were 100% in the pure-GGN group no matter what histological type [8]. Such excellent prognosis naturally makes people think that it is not only the result of surgery, but also that these lesions might be indolent tumors even in the absence of any kind of treatment. Concerns have been raised about the possibility that premature surgical resection may represent‘overtreatment’. This is a good understanding of why Dr. Sepesi takes timing and indications for resection as an important issue for the treatment of GGN [9]. Although the precise surgical indications have not been determined, for obvious reasons a higher ratio of solid component need resected more urgently. The presence of a solid component is associated with a much higher risk for invasive adenocarcinoma [10]. However, there were different measurement results using different attenuation thresholds in regard to defining the solid or ground-glass components. Visual assessment of nodule morphologic structure on chest CT images Is still commonly used in clinical practice. However, interobserver and intraobserver discrepancies in nodule categorization cannot be ignored, especially disagreement on the size and presence of a solid component may lead to different management in the majority of cases with such discrepancies [11]. In order to evaluate the growth rate of GGNs in an accurate, reproducible, and sensitive manner, some measures on three-dimensional volumetry, such as volume doubling time (VDT) and mass doubling time (MDT), are getting more and more applications. High-grade invasive tumors show significantly shorter VDTs and MDTs than do low-grade invasive ones [12]. If the measurements of VDT and MDT can be popularized, they have the potential to become important references for evaluating GGN surgical indications. Furthermore, since the framework combining radiomics with deep learning (RDL) has the potential to predict high-grade lung adenocarcinoma, RDL might be a supplemental tool to screen high-risk subgroup in GGN patients for pathologists in the future [13]. Given the low aggressiveness of GGNs, it has been proposed that some GGNs meeting certain conditions could be cured by a limited surgical resection instead of a major lung resection. The trial of JCOG 0201 made a lot of exploratory work [14,15]. Long-term survival of patients in the trial of JCOG 0201 revealed that radiologic criteria of a consolidation/tumor ratio (CTR) ≤0.25 and a size≤ 2.0 cm or CRT ≤0.50 and a size ≤ 3.0 cm were both able to define a homogeneous subgroup with an excellent prognosis. Whether these radiologic criteria can be validated, we need to wait for the results of some prospective clinical trials, such as JCOG1211 [16] and GALGB140503 (NCT00499330). In term of surgical extent, the extent of lymphadenectomy is also an important issue. In Zhang’s study, there was no lymph node metastasis in GGN patients with CTR≤0.50, regardless of the tumor size [17]. This raises the question as to whether lymph nodes dissection is necessary in patients whose CT features manifest as GGO prominently. In summary, the decision to treat GGNs must consider both the aggressiveness of nodules and competing risks. Although more and more evidence come from retrospective studies on sublobar resection, high-quality evidence is needed to support a paradigm shift in clinical practice. There will be an ever-increasing tumor localization technology development to facilitate care for surgical management of GGNs. GGN, Surgery, Management

Pulmonary Benign Ground-Glass Nodules: CT Features and Pathological Findings.

BackgroundSome pulmonary ground-glass nodules (GGNs) are benign and frequently misdiagnosed due to lack of understanding of their CT characteristics. This study aimed to reveal the CT features and corresponding pathological findings of pulmonary benign GGNs to help improve diagnostic accuracy.Patients and MethodsFrom March 2016 to October 2019, patients with benign GGNs confirmed by operation or follow-up were enrolled retrospectively. According to overall CT manifestations, GGNs were classified into three types: I, GGO with internal high-attenuation zone; II, nodules lying on adjacent blood vessels; and other type, lesions without obvious common characteristics. CT features and pathological findings of each nodule type were evaluated.ResultsAmong the 40 type I, 25 type II, and 14 other type GGNs, 24 (60.0%), 19 (76.0%), and 10 (71.4%) nodules were resected, respectively. Type I GGNs were usually irregular (25 of 40, 62.5%) with only one high-attenuation zone (38 of 40, 95.0%) (main pathological components: thickened alveolar walls with inflammatory cells, fibrous tissue, and exudation), which was usually centric (24 of 40, 60.0%), having blurred margin (38 of 40, 95.0%), and connecting to blood vessels (32 of 40, 80.0%). The peripheral GGO (main pathological component: a small amount of inflammatory cell infiltration with fibrous tissue proliferation) was usually ill-defined (28 of 40, 70.0%). Type II GGNs (main pathological components: focal interstitial fibrosis with or without inflammatory cell infiltration) lying on adjacent vessel branches were usually irregular (19 of 25, 76.0%) and well defined (16 of 25, 64.0%) but showed coarse margins (15 of 16, 93.8%). Other type GGNs had various CT manifestations but their pathological findings were similar to that of type II.ConclusionFor subsolid nodules with CT features manifested in type I or II GGNs, follow-up should be firstly considered in further management.

Myocardial involvement in eosinophilic granulomatosis with polyangiitis evaluated with cardiopulmonary magnetic resonance

Patients with eosinophilic granulomatosis with polyangiitis (EGPA) most commonly die from cardiac causes, however, cardiac involvement remains poorly characterised and the relationship between cardiac and pulmonary disease is not known. This study aimed to characterise myocardial and pulmonary manifestations of EGPA, and their relationship. Prospective comprehensive cardiopulmonary investigation, including a novel combined cardiopulmonary magnetic resonance imaging (MRI) technology, was performed in 13 patients with stable EGPA. Comparison was made with 11 prospectively recruited matched healthy volunteers. Stable EGPA was associated with focal replacement and diffuse interstitial myocardial fibrosis (myocardial extracellular volume 26.9% vs. 24.7%; p = 0.034), which drove a borderline increase in left ventricular mass (56 ± 9 g/m2 vs. 49 ± 8 g/m2; p = 0.065). Corrected QT interval was significantly prolonged and was associated with the severity of myocardial fibrosis (r = 0.582, p = 0.037). Stable EGPA was not associated with increased myocardial capillary permeability or myocardial oedema. Pulmonary tissue perfusion and capillary permeability were normal and there was no evidence of pulmonary tissue oedema or fibrosis. Forced expiratory volume in one second showed a strong inverse relationship with myocardial fibrosis (r = −0.783, p = 0.038). In this exploratory study, stable EGPA was associated with focal replacement and diffuse interstitial myocardial fibrosis, but no evidence of myocardial or pulmonary inflammation or pulmonary fibrosis. Myocardial fibrosis was strongly associated with airway obstruction and abnormal cardiac repolarisation. Further investigation is required to determine the mechanisms underlying the association between heart and lung disease in EGPA and whether an immediate immunosuppressive strategy could prevent myocardial fibrosis formation.

Effect of Levosimendan, an Inodilator, on Streptozotocin‐Induced Diabetic Nephropathy in Rats

Levosimendan, an inodilator, was shown to have a renal protective effect in different models of kidney dysfunction in experimental animals and in patients with heart failure. The aim of this study was to examine the effect of levosimendan on streptozotocin‐induced early diabetic nephropathy. Male Sprague Dawley rats (n = 24, 320–400 g) were randomly distributed into four groups and treated for 6 weeks. Groups 1 and 3 received either vehicle or levosimendan (1 mg/kg/day) for the last three weeks, respectively. Groups 2 and 4 were rendered diabetic by a single i.p. injection of streptozotocin (60 mg/kg) and were treated as in groups 1 and 3, respectively. At the end of the experiment, rats were placed in metabolic cages and urine was collected for biochemical analysis. Rats were then anesthetized and blood samples collected for biochemical analysis. Kidneys were removed for histopathology. In the untreated diabetic group, there was a significant decrease in body weight, polyuria and increased relative kidney weight. There was increased urinary albumin/creatinine ratio (UACR), 24 hour (h) albumin level and N‐acetyl‐β‐D‐glucosaminidase (NAG)/creatinine ratio (UNCR). Streptozotocin did not cause a significant effect on creatinine clearance when adjusted to body weight. In addition, diabetes was associated with increased oxidative stress [reduced plasma total antioxidant capacity (TAC) and catalase activities]. Kidneys from streptozotocin‐treated rats showed focal clear renal tubular cells affecting proximal convoluted tubules and focal mild interstitial fibrosis at the cortico‐medullary junction. Levosimendan significantly attenuated the reduction in body weight, polyuria and the increase in relative kidney weight. In addition, it significantly attenuated the increase in UACR, urinary 24 h albumin level and UNCR in diabetic rats. It also significantly mitigated the decrease in plasma TAC and catalase activities in diabetic rats. Rats in the diabetic group treated with levosimendan showed less clear cell changes but similar interstitial fibrosis when compared with the untreated diabetic group. This study shows that levosimendan ameliorated some of the changes seen in streptozotocin‐induced early diabetic nephropathy in rats. This could be partly due to its antioxidative effects.Support or Funding InformationSupported by an internal grant from Sultan Qaboos University (IG/MED/PHAR/18/01)